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INHIBITION OF RETINOIC ACID RECEPTOR-MEDIATED SIGNALING BY PHTHALATES IN THE TESTIS.
Vo, My-Nuong1, Dufour, Jannette1, Holden, Tarah1, Okita, Janice2, Okita, Richard2, Kim, Kwan Hee1, 1 2
ABSTRACT- Phthalate plasticizers are in the class of chemicals that has become one of the most abundant man-made environmental contaminants. Although phthalates are known to cause peroxisome proliferation, liver cell hyperplasia and hypertrophy, hepatic tumors, and testicular damage in animal studies, the mechanism of action by which phthalates disrupt liver and testicular function remains unknown. It has been shown that vitamin A, the action of which is mediated by retinoic acid receptors (RARs), is essential for normal spermatogenesis, and vitamin A depletion results in germ cell loss and sterility. In this study, we examined the hypothesis that exposure to phthalates interferes with the RAR signaling pathways in the Sertoli cells, causing testicular damage. We investigated the effects of di(2-ethylhexyl) phthalate (DEHP) and mono-(2-ethylhexyl) phthalate (MEHP) on the expression of RAR-regulated genes in the rat testis and in the Sertoli cells, respectively. In addition, we show that MEHP treatment of Sertoli cells disrupts the retinoic acid-induced nuclear localization of RAR
and concomitantly decreases retinoic acid-induced transcriptional activity of RAR. Furthermore, we show by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling analysis that DEHP treatment of rats leads to marked increase in the number of dying germ cells in the testis. These results suggest a possible inhibitory mechanism of action for phthalates in the testis which may lead to increased apoptosis of germ cells.
KEY WORDS: Testis, Phthalates, Vitamin A, Retinoic acid receptor